Chronic hyperglycemia is believed to reduce both insulin secretion and insulin sensitivity, which in turn will cause elevation of blood glucose levels and lead to exacerbation of diabetes. Drugs conventionally used as therapeutic agents for diabetes include biguanides, sulfonylureas, glycosidase inhibitors and insulin-resistance improving agents. However, adverse side effects of these drugs have been reported; for example, lactic acidosis for biguanides, hypoglycemia for sulfonylureas, as well as diarrhea and serious hepatic dysfunction for glycosidase inhibitors. It is therefore desirable to develop therapeutic agents for diabetes that depend on a new mechanism of action which is different from those conventionally proposed.
Phloridzin, a glucose derivative isolated from nature, has been identified as having a hypoglycemic effect by inhibiting excessive glucose reabsorption in the kidney to accelerate the glucose excretion (J. Clin. Invest., vol. 80, p. 1037, 1987; J. Clin. Invest., vol. 87, p. 1510, 1987). There have been indications that this glucose reabsorption event is mediated by sodium-dependent glucose transporter 2 (SGLT2) present at the S1 site of renal proximal tubules (J. Clin. Invest., vol. 93, p. 397, 1994).
Under these backgrounds, an increasing number of studies have been conducted to develop therapeutic agents for diabetes that depend on SGLT2 inhibition, and a large number of phloridzin derivatives have been reported (see European Patent Publication No. EP0850948, International Patent Publication Nos. WO0168660, WO0116147, WO0174834, WO0174835, WO0253573, WO0268439, WO0268440, WO0236602 and WO0288157).
When administered orally, phloridzin derivatives are hydrolyzed at glycosidic linkages by the action of glycosidase present in the small intestine, thus resulting in low absorption efficiency of unchanged form and a weak hypoglycemic effect. For this reason, various attempts have been made, for example, to increase absorption efficiency by administering phloridzin derivatives in the form of prodrugs and/or to prevent digestion by synthesizing compounds replaced by carbon-carbon linkages instead of glycosidic linkages (see United States Patent No. US20010041674, International Patent Publication Nos. WO0127128 and WO0283066).
However, since no chemical synthesis technique has been developed for β-selective glycosylation of 5-thioglucose derivatives in which the ring oxygen atom of glucose is replaced by a sulfur atom, there is no report on heteroaryl 5-thio-β-D-glucopyranoside derivatives. Thus, there is also no report on the SGLT2-inhibiting effect of heteroaryl 5-thio-β-D-glucopyranoside derivatives.